Department of Anaesthesiology and Intensive Care Medicine, Tübingen University Hospital, Eberhard-Karls University Tübingen, Tübingen, Germany.
Department of Anaesthesiology, Ludwig-Maximilians-University, Muenchen, Germany.
Nat Commun. 2018 Feb 26;9(1):816. doi: 10.1038/s41467-018-03105-2.
Myocardial ischemia-reperfusion injury (IRI) leads to the stabilization of the transcription factors hypoxia-inducible factor 1-alpha (HIF1-alpha) and hypoxia-inducible factor 2-alpha (HIF2-alpha). While previous studies implicate HIF1-alpha in cardioprotection, the role of HIF2-alpha remains elusive. Here we show that HIF2-alpha induces the epithelial growth factor amphiregulin (AREG) to elicit cardioprotection in myocardial IRI. Comparing mice with inducible deletion of Hif1a or Hif2a in cardiac myocytes, we show that loss of Hif2-alpha increases infarct sizes. Microarray studies in genetic models or cultured human cardiac myocytes implicate HIF2-alpha in the myocardial induction of AREG. Likewise, AREG increases in myocardial tissues from patients with ischemic heart disease. Areg deficiency increases myocardial IRI, as does pharmacologic inhibition of Areg signaling. In contrast, treatment with recombinant Areg provides cardioprotection and reconstitutes mice with Hif2a deletion. These studies indicate that HIF2-alpha induces myocardial AREG expression in cardiac myocytes, which increases myocardial ischemia tolerance.
心肌缺血再灌注损伤（IRI）导致转录因子缺氧诱导因子 1-α（HIF1-α）和缺氧诱导因子 2-α（HIF2-α）的稳定。虽然先前的研究表明 HIF1-α在心脏保护中起作用，但 HIF2-α的作用仍不清楚。在这里，我们表明 HIF2-α诱导表皮生长因子 Amphiregulin（AREG）在心肌 IRI 中引起心脏保护作用。通过比较心肌细胞中诱导型缺失 Hif1a 或 Hif2a 的小鼠，我们表明 Hif2-α的缺失会增加梗死面积。遗传模型或培养的人类心肌细胞中的基因芯片研究表明 HIF2-α参与了 AREG 在心肌中的诱导。同样，从缺血性心脏病患者的心肌组织中也发现 AREG 增加。Areg 缺乏会增加心肌 IRI，而 Areg 信号转导的药理学抑制也是如此。相比之下，用重组 Areg 治疗可提供心脏保护并重建 Hif2a 缺失的小鼠。这些研究表明，HIF2-α在心肌细胞中诱导心肌 AREG 表达，从而增加心肌缺血耐受。
